scholarly journals Sequential Delivery of Dual Growth Factors from Injectable Chitosan-Based Composite Hydrogels

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 365 ◽  
Author(s):  
Qing Min ◽  
Jiaoyan Liu ◽  
Xiaofeng Yu ◽  
Yuchen Zhang ◽  
Jiliang Wu ◽  
...  
Keyword(s):  
Bone Repair ◽  
In Vitro Release ◽  
C2c12 Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Temporal Separation ◽  
Composite Gels ◽  
Sequential Release ◽  
Morphogenetic Protein ◽  
Chemotactic Effect

Local administration of platelet-derived growth factor-BB (PGDF-BB) and bone morphogenetic protein-2 (BMP-2) in a sequential release manner could substantially promote bone healing. To achieve this goal, a delivery system that could sustain the release of PGDF-BB and BMP-2 by way of temporal separation was developed. One type of PGDF-BB-encapsulated alginate microsphere and another type of BMP-2-encapsulated microsphere with a core-shell structure were respectively produced using emulsification methods. These two types of microspheres were then embedded into chitosan/glycerophosphate hydrogel for constructing composite gels. Some of them were found to be injectable at ambient temperature and had thermo-sensitive features near physiological temperature and pH. The optimally formulated composite gels showed the ability to control the release of PGDF-BB and BMP-2 in a sequential fashion in which PDGF-BB was released earlier than BMP-2. In vitro release patterns indicated that the release rates could be significantly regulated by varying the embedded amount of the factor-encapsulated microspheres, which can in turn mediate the temporal separation release interval between PGDF-BB and BMP-2. The released PDGF-BB and BMP-2 were detected to be bioactive based on their respective effects on Balb/c 3T3 and C2C12 cells. These results suggest that the presently developed composite gels have the potential for bone repair by synergistically utilizing the early chemotactic effect of PDGF-BB and the subsequent osteogenic and angiogenic functions of PDGF-BB and BMP-2.

scholarly journals Efficacy of rhBMP-2 Loaded PCL/β-TCP/bdECM Scaffold Fabricated by 3D Printing Technology on Bone Regeneration

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Eun-Bin Bae ◽  
Keun-Ho Park ◽  
Jin-Hyung Shim ◽  
Ho-Yun Chung ◽  
Jae-Won Choi ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Release Kinetics ◽  
In Vitro Release ◽  
Bone Morphogenetic Protein 2 ◽  
Sprague Dawley ◽  
Calvarial Bone ◽  
Decellularized Extracellular Matrix ◽  
Morphogenetic Protein ◽  
Rat Calvarial Defect

This study was undertaken to evaluate the effect of 3D printed polycaprolactone (PCL)/β-tricalcium phosphate (β-TCP) scaffold containing bone demineralized and decellularized extracellular matrix (bdECM) and human recombinant bone morphogenetic protein-2 (rhBMP-2) on bone regeneration. Scaffolds were divided into PCL/β-TCP, PCL/β-TCP/bdECM, and PCL/β-TCP/bdECM/BMP groups. In vitro release kinetics of rhBMP-2 were determined with respect to cell proliferation and osteogenic differentiation. These three reconstructive materials were implanted into 8 mm diameter calvarial bone defect in male Sprague-Dawley rats. Animals were sacrificed four weeks after implantation for micro-CT, histologic, and histomorphometric analyses. The findings obtained were used to calculate new bone volumes (mm3) and new bone areas (%). Excellent cell bioactivity was observed in the PCL/β-TCP/bdECM and PCL/β-TCP/bdECM/BMP groups, and new bone volume and area were significantly higher in the PCL/β-TCP/bdECM/BMP group than in the other groups (p<.05). Within the limitations of this study, bdECM printed PCL/β-TCP scaffolds can reproduce microenvironment for cells and promote adhering and proliferating the cells onto scaffolds. Furthermore, in the rat calvarial defect model, the scaffold which printed rhBMP-2 loaded bdECM stably carries rhBMP-2 and enhances bone regeneration confirming the possibility of bdECM as rhBMP-2 carrier.

scholarly journals Enhanced BMP-2-Mediated Bone Repair Using an Anisotropic Silk Fibroin Scaffold Coated with Bone-like Apatite

2021 ◽  
Vol 23 (1) ◽  
pp. 283
Author(s):  
Christian Deininger ◽  
Andrea Wagner ◽  
Patrick Heimel ◽  
Elias Salzer ◽  
Xavier Monforte Vila ◽  
...  
Keyword(s):  
Bone Repair ◽  
Bone Morphogenetic Protein 2 ◽  
Great Promise ◽  
Calcium Phosphate Coating ◽  
Graft Material ◽  
Morphogenetic Protein ◽  
Silk Scaffolds ◽  
Cost Efficient

The repair of large bone defects remains challenging and often requires graft material due to limited availability of autologous bone. In clinical settings, collagen sponges loaded with excessive amounts of bone morphogenetic protein 2 (rhBMP-2) are occasionally used for the treatment of bone non-unions, increasing the risk of adverse events. Therefore, strategies to reduce rhBMP-2 dosage are desirable. Silk scaffolds show great promise due to their favorable biocompatibility and their utility for various biofabrication methods. For this study, we generated silk scaffolds with axially aligned pores, which were subsequently treated with 10× simulated body fluid (SBF) to generate an apatitic calcium phosphate coating. Using a rat femoral critical sized defect model (CSD) we evaluated if the resulting scaffold allows the reduction of BMP-2 dosage to promote efficient bone repair by providing appropriate guidance cues. Highly porous, anisotropic silk scaffolds were produced, demonstrating good cytocompatibility in vitro and treatment with 10× SBF resulted in efficient surface coating. In vivo, the coated silk scaffolds loaded with a low dose of rhBMP-2 demonstrated significantly improved bone regeneration when compared to the unmineralized scaffold. Overall, our findings show that this simple and cost-efficient technique yields scaffolds that enhance rhBMP-2 mediated bone healing.

scholarly journals PLGA-BMP-2 and PLA-17β-Estradiol Microspheres Reinforcing a Composite Hydrogel for Bone Regeneration in Osteoporosis

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 648 ◽  
Author(s):  
Patricia García-García ◽  
Ricardo Reyes ◽  
Elisabet Segredo-Morales ◽  
Edgar Pérez-Herrero ◽  
Araceli Delgado ◽  
...  
Keyword(s):  
Release Kinetics ◽  
In Vitro Release ◽  
Bone Morphogenetic Protein 2 ◽  
Poly Lactic Acid ◽  
Core System ◽  
Morphogenetic Protein ◽  
17Β Estradiol ◽  
Second Phases

The controlled release of active substances—bone morphogenetic protein 2 (BMP-2) and 17β-estradiol—is one of the main aspects to be taken into account to successfully regenerate a tissue defect. In this study, BMP-2- and 17β-estradiol-loaded microspheres were combined in a sandwich-like system formed by a hydrogel core composed of chitosan (CHT) collagen, 2-hidroxipropil γ-ciclodextrin (HP-γ-CD), nanoparticles of hydroxyapatite (nano-HAP), and an electrospun mesh shell prepared with two external electrospinning films for the regeneration of a critical bone defect in osteoporotic rats. Microspheres were made with poly-lactide-co-glycolide (PLGA) to encapsulate BMP-2, whereas the different formulations of 17β-estradiol were prepared with poly-lactic acid (PLA) and PLGA. The in vitro and in vivo BMP-2 delivered from the system fitted a biphasic profile. Although the in vivo burst effect was higher than in vitro the second phases (lasted up to 6 weeks) were parallel, the release rate ranged between 55 and 70 ng/day. The in vitro release kinetics of the 17β-estradiol dissolved in the polymeric matrix of the microspheres depended on the partition coefficient. The 17β-estradiol was slowly released from the core system using an aqueous release medium (Deff = 5.58·10−16 ± 9.81·10−17m2s−1) and very fast in MeOH-water (50:50). The hydrogel core system was injectable, and approximately 83% of the loaded dose is uniformly discharged through a 20G needle. The system placed in the defect was easily adapted to the defect shape and after 12 weeks approximately 50% of the defect was refilled by new tissue. None differences were observed between the osteoporotic and non-osteoporotic groups. Despite the role of 17β-estradiol on the bone remodeling process, the obtained results in this study suggest that the observed regeneration was only due to the controlled rate released of BMP-2 from the PLGA microspheres.

scholarly journals Material-driven fibronectin assembly for high-efficiency presentation of growth factors

2016 ◽  
Vol 2 (8) ◽  
pp. e1600188 ◽  
Author(s):  
Virginia Llopis-Hernández ◽  
Marco Cantini ◽  
Cristina González-García ◽  
Zhe A. Cheng ◽  
Jingli Yang ◽  
...  
Keyword(s):  
Growth Factors ◽  
Bone Repair ◽  
High Efficiency ◽  
Underlying Mechanism ◽  
Ethyl Acrylate ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
High Doses

Growth factors (GFs) are powerful signaling molecules with the potential to drive regenerative strategies, including bone repair and vascularization. However, GFs are typically delivered in soluble format at supraphysiological doses because of rapid clearance and limited therapeutic impact. These high doses have serious side effects and are expensive. Although it is well established that GF interactions with extracellular matrix proteins such as fibronectin control GF presentation and activity, a translation-ready approach to unlocking GF potential has not been realized. We demonstrate a simple, robust, and controlled material-based approach to enhance the activity of GFs during tissue healing. The underlying mechanism is based on spontaneous fibrillar organization of fibronectin driven by adsorption onto the polymer poly(ethyl acrylate). Fibrillar fibronectin on this polymer, but not a globular conformation obtained on control polymers, promotes synergistic presentation of integrin-binding sites and bound bone morphogenetic protein 2 (BMP-2), which enhances mesenchymal stem cell osteogenesis in vitro and drives full regeneration of a nonhealing bone defect in vivo at low GF concentrations. This simple and translatable technology could unlock the full regenerative potential of GF therapies while improving safety and cost-effectiveness.

scholarly journals Biomimetic Mineralization on 3d Printed Pla Scaffolds: On the Response of Human Primary Osteoblasts Spheroids and in Vivo Implantation

2020 ◽  
Author(s):  
Marianna O. C. Maia-Pinto ◽  
Ana Carolina B. Brochado ◽  
Bruna Nunes Teixeira ◽  
Suelen C. Sartoretto ◽  
Marcelo J. Uzeda ◽  
...  
Keyword(s):  
Bone Repair ◽  
In Vitro Release ◽  
Biological Response ◽  
Bone Morphogenetic Protein 2 ◽  
Primary Osteoblast ◽  
Rat Calvaria ◽  
3D Printed ◽  
Human Primary Osteoblast

This study aimed to assess the response of 3D printed PLA scaffolds biomimetically coated with apatite on human primary osteoblast spheroids and evaluate the biological response to its association with Bone Morphogenetic Protein 2 (rhBMP-2) in rat calvaria. PLA scaffolds were produced via 3D printing, soaked in simulated body fluid (SBF) solution, and characterized by physical-chemical, morphological, and mechanical properties. The in vitro biological response was assessed with human primary osteoblast (HOb) spheroids. The in vivo analysis was conducted through the implantation of 3D printed PLA scaffolds either alone, covered by apatite (PLA-CaP) or PLA-CaP loaded with rhBMP-2 (PLA-CaP+rhBMP-2) on critical-sized defects (8 mm) of rat calvaria. Increased cell adhesion and in vitro release of growth factors (PDGF, bFGF, VEGF) was observed for PLA-CaP scaffolds when pre-treated with FBS. PLA-CaP+BMP2 presented higher values of newly formed bone (NFB) than other groups at all experimental periods (p&amp;lt;0.05), attaining 44.85% of NFB after 6 months. These findings indicate that functionalization of PLA scaffolds with biomimetic apatite can improve its biological properties in the presence of complex biological media. Its association with BMP2 may enhance bone repair, suggesting this strategy as a promising candidate for bone tissue engineering.

scholarly journals The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 979
Author(s):  
Patricia Garcia-Garcia ◽  
Ricardo Reyes ◽  
José Antonio Rodriguez ◽  
Tomas Martín ◽  
Carmen Evora ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Growth Promotion ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Therapeutic Molecules ◽  
Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

BMP2 Is Required for Postnatal Maintenance of Osteochondral Tissues of the Temporomandibular Joint

Cartilage ◽  
2020 ◽  
pp. 194760352098015
Author(s):  
Mara H. O’Brien ◽  
Eliane H. Dutra ◽  
Shivam Mehta ◽  
Po-Jung Chen ◽  
Sumit Yadav
Keyword(s):  
Age Groups ◽  
Mandibular Condyle ◽  
Bone Morphogenetic Protein 2 ◽  
Matrix Synthesis ◽  
Cartilage Growth ◽  
Chondrocyte Proliferation ◽  
Conditional Deletion ◽  
Morphogenetic Protein

Objective Bone morphogenetic protein 2 (BMP2) plays important roles in cartilage growth and development. Paradoxically, elevated levels of BMP2 leads to hypertrophic differentiation and osteoarthritis of cartilage. We examined the in vivo loss of BMP2 in cells expressing aggrecan of the mandibular condyle and knee. Design Three-week-old BMP2 flox/flox- CreER-positive mice and their Cre-negative littermates were treated with tamoxifen and raised until 3 or 6 months. We also investigated the direct effects of BMP2 on chondrocytes in vitro. Cells from the mandibular condyle of mice were treated with recombinant human BMP2 (rhBMP2) or rhNoggin (inhibitor of BMP2 signaling). Results Conditional deletion of BMP2 caused breakage of the cartilage integrity in the mandibular condyle of mice from both age groups, accompanied by a decrease in cartilage thickness, matrix synthesis, mineralization, chondrocyte proliferation, and increased expression of degeneration markers, while the effects at articular cartilage were not significant. In vitro results revealed that rhBMP2 increased chondrocyte proliferation, mineralization, and differentiation, while noggin induced opposite effects. Conclusions In conclusion, BMP2 is essential for postnatal maintenance of the osteochondral tissues of the mandibular condyle.

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